SUMMARY Smoking is addictive and most smokers would like to quit. However, even with treatment, only a small percentage of smokers quits successfully. Clinical studies indicate that smoking cessation leads to anhedonia, which increases the risk for relapse. Nicotine induces the release of dopamine (DA), which plays a role in establishing habitual smoking, while the activation of stress systems has been suggested to mediate withdrawal and anhedonia. Virtually all animal studies have been conducted with nondependent rodents that had limited or short access to nicotine. Therefore, very little is known about the mechanisms that mediate withdrawal and self-administration in dependent animals with high levels of nicotine intake. To develop new smoking cessation treatments, more insight is needed into the neurobiological mechanisms that mediate withdrawal and nicotine intake in animals that have become dependent by self-administering nicotine. The long-term goal of this research program is to determine the adaptations in the reward system that cause high levels of nicotine intake and anhedonia in dependent animals. The objective of our studies is to determine the role of DA and the stress hormone corticosterone (CORT) in nicotine self-administration in dependent animals and withdrawal-induced anhedonia. It is proposed to use an intermittent long access model to obtain high levels of nicotine intake and induce dependence. Our preliminary studies point to a role for DA in high levels of nicotine intake in dependent animals, and brain stress systems in the anhedonia associated with withdrawal. Based on our studies, it is hypothesized that DA transmission and glucocorticoid receptor (GR) signaling in the nucleus accumbens (Nacc) are pivotal for high levels of nicotine intake and anhedonia associated with nicotine withdrawal. Three aims are proposed to test this hypothesis. 1) Determine the relationship between nicotine intake and reward function in dependent (long access) and nondependent (short access) animals. 2) Determine the role of DA signaling in nicotine intake in dependent and nondependent animals. 3) Determine the role of DA-CORT interactions in the Nacc in nicotine intake and anhedonia in dependent and nondependent animals. To investigate the relationship between nicotine intake and reward function, male and female rats will be prepared with intravenous catheters and intracranial self-stimulation (ICSS) electrodes. The ICSS method provides an objective measure of reward function. Dopamine antagonists and transgenic D1-Cre and D2-Cre rats will be used to determine the role of D1 and D2 neurons in the Nacc in high levels of nicotine intake and withdrawal. It is predicted that D1 receptors play a critical role in nicotine intake in dependent and nondependent animals. It is also expected that blockade of GR will decrease nicotine intake in dependent animals, prevents the decrease in DA levels in the Nacc during withdrawal, and diminishes anhedonia associated with nicotine withdrawal. The studies will provide insight into the role of DA and CORT in the Nacc in high levels of nicotine self-administration in dependent animals and withdrawal-induced anhedonia.